Recent advances in therapeutic engineered extracellular vesicles.

Extracellular vesicles (EVs) are natural particles secreted by living cells, which hold significant potential for various therapeutic applications. Native EVs have specific components and structures, allowing them to cross biological barriers, and circulate in vivo for a long time. Native EVs have also been bioengineered to enhance their therapeutic efficacy and targeting affinity. Recently, the therapeutic potential of surface-engineered EVs has been explored in the treatment of tumors, autoimmune diseases, infections and other diseases by ongoing research and clinical trials. In this review, we will introduce the modified methods of engineered EVs, summarize the application of engineered EVs in preclinical and clinical trials, and discuss the opportunities and challenges for the clinical translation of surface-engineered EVs.

P7C3 Ameliorates Bone Loss by Inhibiting Osteoclast Differentiation and Promoting Osteogenesis.

Bone homeostasis, the equilibrium between bone resorption and formation, is essential for maintaining healthy bone tissue in adult humans. Disruptions of this process can lead to pathological conditions such as osteoporosis. Dual-targeted agents, capable of inhibiting excessive bone resorption and stimulating bone formation, are being explored as a promising strategy for developing new treatments to address osteoporosis. In this study, we investigated the effects of P7C3 on bone remodeling and its potential therapeutic role in osteoporosis treatment in mice. Specifically, P7C3 can remarkably suppress receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast differentiation in bone marrow macrophages via the Akt-NF-κB-NFATc1 signaling pathway. Additionally, RNA sequencing (RNAseq) analysis revealed that P7C3 promoted osteoblast differentiation and function through the Wnt/ß-catenin signaling pathway, thereby enhancing bone formation. Furthermore, µCT analysis and histological examination of bone tissues from P7C3-treated mice showed attenuation of both Ti-induced bone erosion and ovariectomy (OVX)-induced bone loss. These findings suggest that P7C3 may have a novel function in bone remodeling and may be a promising therapeutic agent for the treatment of osteoporosis. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Neurological disorders after severe pneumonia are associated with translocation of endogenous bacteria from the lung to the brain.

Neurological disorders are a common feature in patients who recover from severe acute pneumonia. However, the underlying mechanisms remain poorly understood. Here, we show that the neurological syndromes after severe acute pneumonia are partly attributed to the translocation of endogenous bacteria from the lung to the brain during pneumonia. Using principal components analysis, similarities were found between the brain's flora species and those of the lungs, indicating that the bacteria detected in the brain may originate from the lungs. We also observed impairment of both the lung-blood and brain-blood barriers, allowing endogenous lung bacteria to invade the brain during pneumonia. An elevated microglia and astrocyte activation signature via bacterial infection-related pathways was observed, indicating a bacterial-induced disruption of brain homeostasis. Collectively, we identify endogenous lung bacteria that play a role in altering brain homeostasis, which provides insight into the mechanism of neurological syndromes after severe pneumonia.

PD-L1-Expressing Extracellular Vesicles for the Treatment of Pneumonia.

Acute respiratory distress syndrome (ARDS) is a severe lung condition with a high mortality rate and a lack of effective drug therapy. In this work, we developed mesenchymal stem cell (MSC)-derived extracellular vesicles with high PD-L1 expression (MSC-EVs-PD-L1) for treating lipopolysaccharide (LPS)-induced pneumonia by intratracheal administration. We found an upregulation of PD-1 expression in the inflammatory region of murine lungs; hence, MSC-EVs-PD-L1 exerted immunosuppressive effects via the PD-1/PD-L1 signaling pathway. Furthermore, we treated LPS-induced pneumonia mice by intratracheal administration, which enabled heavy drug accumulation in the lungs of mice and better therapeutic efficacy compared to systemic administration. Our results suggest that MSC-EVs-PD-L1 has the potential to provide a universal platform technology for the immunotherapy of pneumonia.

Platelet-derived extracellular vesicles for drug delivery.

Platelet-derived extracellular vesicles (PEVs) are a subset of EVs that are released from platelets, which are small nuclear cell fragments that play a critical role in hemostasis and thrombosis. PEVs have been shown to have important roles in a variety of physiological and pathological processes, including inflammation, angiogenesis, and cancer. Recently, researchers, including our group have utilized PEVs as drug delivery platforms as PEVs could target inflammatory sites both passively and actively. This review summarizes the biological function of PEVs, introduces recent applications of PEVs in targeted drug delivery, and provides an outlook for the further development of utilizing PEVs for drug delivery.

Severe pneumonia induces immunosenescence of T cells in the lung of mice.

Severe pneumonia may induce sequelae and accelerated aging process even after the person has recovered. However, the underline mechanism is not very clear. More research is needed to fully understand the long-term effects of severe pneumonia. In this study, we found that mice recovered from severe pneumonia showed lung immunosenescence, which was characterized by a bias naive-memory balance of T lymphocytes in the lung. The reduction of naïve T cells is associated with the diminished immune response to cancer or external new antigens, which is one of the key changes that occurs with age. Our results also indicate the link between severe pneumonia and aging process, which is mediated by the disrupted T cells homeostasis in the lungs after pneumonia.

SnSe Nanosheets Mimic Lactate Dehydrogenase to Reverse Tumor Acid Microenvironment Metabolism for Enhancement of Tumor Therapy.

The acidic tumor microenvironment (TME) is unfriendly to the activity and function of immune cells in the TME. Here, we report inorganic nanozymes (i.e., SnSe NSs) that mimic the catalytic activity of lactate dehydrogenase to degrade lactate to pyruvate, contributing to the metabolic treatment of tumors. As found in this study, SnSe NSs successfully decreased lactate levels in cells and tumors, as well as reduced tumor acidity. This is associated with activation of the immune response of T cells, thus alleviating the immunosuppressive environment of the TME. More importantly, the nanozyme successfully inhibited tumor growth in mutilate mouse tumor models. Thus, SnSe NSs show a promising result in lactate depletion and tumor suppression, which exemplifies its potential strategy in targeting lactate for metabolic therapy.

Targeted delivery of dexamethasone in acute pneumonia.

Pneumonia has contributed to significant mortality owing to the irreversible injury to the lungs and severe inflammation of the tissue. Dexamethasone (DEX) is regarded as an effective drug to relieve the level of pneumonia, while the adverse effect of which is non-negligible. Here, we developed a targeted delivery strategy based on platelet-derived extracellular vesicles (PEVs), which are naturally occurring nanoparticles released by platelets, for DEX delivery in acute pneumonia, aiming to reduce the side effects and improve the therapeutic efficacy. Our strategy may shed light on the problems in DEX-based acute pneumonia therapy clinically.